This research is drected toward understanding the mechanisms by which the immune system initiates and controls inflammatory responses. Specifically, we will define the biochemical mechanism involved in the chemotaxis of leukocytes such as polymorphonuclear leucocytes, monocytes and macrophages. We will characterize the chemotactic factor receptors on leukocytes and see if abnormalities of such receptors are associated with inflammatory diseases such as periodontosis. We have recently demonstrated that transmethylation reactions mediated by S-adenosyl methionine are required for directed movement by human monocytes, guinea pig macrophages and guinea pig granulocytes. Phagocytosis, on the other hand, has far less stringent requirements for methylation indicating that chemotaxis and phagocytosis have different metabolic requirements. We have also shown that phospholipid methylation by leukocytes is altered upon their exposure to chemotactic factors. Production of phosphatidylcholine from phosphatidylethanolamine is inhibited in guinea pig macrophages by up to 70% following incubation with chemotactic factors. Changes in phospholipid composition following the binding of chemotactic factors may produce biophysical alterations in the membrane which are necessary for polarized cellular motility. We now seek to determine how chemotactic factors inhibit phospholipid methylation and exactly what role alterations in cellular phospholipid composition play in chemotaxis. In studies concerning the mechanisms of host resistance to endotoxin, it was found that in normal mice, "native" endotoxin markedly suppresses the magnitude of intraperitoneal inflammatory responses to other inflammatory agents, whereas in "non-responder" C3H/HeJ mice, endotoxin does not suppress inflammation. The polysaccharide moiety of the endotoxin molecule is required for the suppressive effects. The mechanism by which endotoxin suppresses inflammation in normal mice is being investigated. In sum, the studies described here will elucidate biochemical mechanisms of inflammation and attempt to characterize the factors which govern the effectiveness and intensity of inflammatory reactions.